Our in vitro investigations suggest that prolonged exposure of cells to AZT increases thymidine kinase (TK) activity, the enzyme catalyzing the first step in the sequential phosphorylation of AZT to its active metabolite, AZT-5'-triphosphate (AZT-TP). Thus, TK activity is one of the major determinants of AZT's chemotherapeutic response. Therefore, an important question of clinical relevance is: Does the long term use of AZT also alter lymphocytic TX activity in the patients who are on AZT therapy. Enhanced phosphorylation of AZT or thymidine may yield high intracellular concentrations of AZT-TP and/or thymidine-5'-triphosphate (TTP). Changes in the intracellular AZT-TP and TTP may affect other intracellular nucleotide pool, increase or reduce effectiveness or drug toxicity and require dose adjustment. In order to examine some of these questions, we propose to initiate the following pilot study: (i) to follow TK activity in the lymphocytes of asymptomatic HIV seropositive patients who are on AZT at entry and at 3, 6, and 9 months during therapy; and (ii) determine intracellular accumulation of AZT-TP and TTP in the patients lymphocytes and in H9 cells grown in vitro. Lymphocytes will be isolated from 15 ml heparinized blood obtained from HIV seropositive asymptomatic patients who are on AZT therapy (through an ongoing ACTG study at our institution). TK will be assayed in the lysates of the cells and lymphocytes using [methyl-3H] TdR or AZT. Incorporation of tritiated TdR or AZT in the lymphocytic and H9 cellular nucleotide pool will be followed by HPLC. These investigations will enhance our understanding on the effects of long term use of AZT on its own efficacy and suggest strategies for needed modifications in therapy.